期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 120, 期 7, 页码 2516-2527出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI41078
关键词
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资金
- Bundesministerium fur Bildung und Forschung
- Deutsche Forschungsgemeinschaft [Ba1433/5]
- Austrian Science Foundation [SFB021]
- Max Planck Society
- Cancer Research UK
Tumor cell resistance to ionizing radiation and chemotherapy is a major obstacle in cancer therapy. One factor contributing to this is integrin-mediated adhesion to ECM. The adapter protein particularly interesting new cysteine-histidine-rich 1 (PINCH1) is recruited to integrin adhesion sites and promotes cell survival, but the mechanisms underlying this effect are not well understood. Here we have shown that PINCH1 is expressed at elevated levels in human tumors of diverse origins relative to normal tissue. Furthermore, PINCH1 promoted cell survival upon treatment with ionizing radiation in vitro and in vivo by perpetuating Akt1 phosphorylation and activity. Mechanistically, PINCH1 was found to directly bind to protein phosphatase la (PP1 alpha) - an Akt1-regulating protein - and inhibit PP1 alpha activity, resulting in increased Akt1 phosphorylation and enhanced radioresistance. Thus, our data suggest that targeting signaling molecules such as PINCH1 that function downstream of focal adhesions (the complexes that mediate tumor cell adhesion to ECM) may overcome radio- and chemoresistance, providing new therapeutic approaches for cancer.
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